Cost effectiveness of a 21-valent pneumococcal conjugate vaccine in adults

Abstract

Background: In July 2024, Health Canada authorized a 21-valent pneumococcal conjugate vaccine (Pneu-C-21) for use in adults.

Objective: To conduct a systematic review of the cost-effectiveness of Pneu-C-21 for preventing pneumococcal disease in adults.

Methods: We conducted a systematic search of the literature and National Immunization Technical Advisory Groups’ websites on July 3, 2024. We included economic evaluations that assessed Pneu-C-21 as a vaccination strategy among adults aged 18 years and older. Costs were adjusted to 2023 Canadian dollars.

Results: We identified 10 studies in our search, five of which were summarized in our review. No economic evaluations were conducted in Canada. All economic evaluations used static cohort models and incorporated indirect effects from paediatric pneumococcal conjugate vaccination in primary or sensitivity analyses. Although incremental cost-effectiveness ratios were heterogeneous across included economic evaluations, overall, they qualitatively identified the same vaccination strategies as optimal within the given age and risk groups. Pneu-C-21 is likely to be cost-effective in adults aged 65 years and older and adults under the age of 65 years with specific high risk conditions.

Conclusion: Pneu-C-21 is likely to be cost-effective in adults within specific age and risk groups. The applicability of the included economic evaluations to adults living in Canada is limited because the serotype-specific incidence of pneumococcal disease and the impact of indirect effects from pediatric vaccination varies by region and over time.

Introduction

The bacterium Streptococcus pneumoniae is a significant cause of morbidity and mortality in Canada and worldwide ^{Footnote 1}. Of over 100 known serotypes of S. pneumoniae ^{Footnote 2}, 15 cause the majority of disease in Canada ^{Footnote 1}. The upper respiratory tracts of between 20%–60% of children and approximately 10% of healthy adults are colonized with S. pneumoniae ^{Footnote 3}. In rare cases, there is infection of a normally sterile site (e.g., blood, meninges), causing invasive pneumococcal disease (IPD).

There are a number of pneumococcal vaccines authorized for use in Canada, including the 15- and 20-valent pneumococcal conjugate vaccines (Pneu-C-15 and Pneu-C-20, respectively) and the 23-valent pneumococcal polysaccharide vaccine (Pneu-P-23) ^{Footnote 4}, that aim to protect vaccine recipients from severe disease caused by 15-, 20- or 23-valent S. pneumoniae serotypes. Canada’s National Advisory Committee on Immunization (NACI) currently recommends the use of Pneu-C-20 in adults at high risk of IPD, including adults aged 65 years and older and adults under 65 years of age with medical or social risk factors.

In July 2024, Health Canada approved a 21-valent pneumococcal conjugate vaccine (Pneu-C-21) for use in individuals aged 18 years and older ^{Footnote 5}. One month prior, in June 2024, the United States Advisory Committee on Immunization Practices recommended Pneu-C-21 as an option for adults aged 19 years and older who were recommended to receive Pneu-C-15 or Pneu-C-20 ^{Footnote 6}. Pneu-C-21 contains 10 unique non-cross-reactive serotypes (9N, 15A, 16F, 17F, 20A, 23A, 23B, 24F, 31 and 35B) compared to Pneu-C-20, and Pneu-C-20 contains nine unique serotypes not included in Pneu-C-21 (1, 4, 5, 6B, 9V, 14, 18C, 19F and 23F). Using established methodology to assess the benefit of Pneu-C-21 in public health programs ^{Footnote 7}, NACI sought to update recommendations on the use of pneumococcal vaccines in adults as part of its mandate. Economic evidence was determined to be a necessary component to inform the development of the vaccine guidance.

In support of NACI’s workplan ^{Footnote 8}, Canada’s Drug Agency (CDA; formerly Canadian Agency for Drugs and Technologies in Health) conducted a systematic review on the cost-effectiveness of pneumococcal conjugate vaccines in adults at high risk for pneumococcal disease (PD) aged 18 to 64 years ^{Footnote 9}. The systematic review generally found that Pneu-C-13, alone or in combination with Pneu-P-23, and Pneu-C-20 may be cost-effective compared to no vaccination at a threshold of $50,000/quality-adjusted life year (QALY) gained in populations at higher risk of IPD ^{Footnote 9}. Pneu-C-15 used in combination with Pneu-P-23 was unlikely to be cost effective at commonly used thresholds in high-risk adults. None of the included economic evaluations included Pneu-C-21 as an intervention or comparator.

The CDA systematic review focused on the question of whether pneumococcal conjugate vaccines are a cost-effective intervention in adults less than 65 years of age at risk for PD. We conducted a separate systematic review to address the policy question of whether Pneu-C-21 is cost-effective for preventing PD in adults aged 18 years and older. The aim of this review was to identify any more recently published studies and include all adults, including those aged 65 years and older.

Methods

Our systematic review was informed by NACI’s Guidelines for Systematic Reviews on Economic Evaluations of Vaccination Programs ^{Footnote 10}. We conducted a literature search of EBM Reviews; Cochrane Central Register of Controlled Trials, EconLit, Embase, International Pharmaceutical Abstracts, Ovid MEDLINE and Scopus. In addition, we searched the websites of National Immunization Technical Advisory Groups, including the Joint Committee on Immunisation (United Kingdom), the Advisory Committee on Immunization Practices (ACIP; United States), Standing Committee on Immunization (Germany) and Australian Technical Advisory Group on Immunisation (Australia). Our search was limited to literature published in English and French from 2019 onward. The search strategy was developed in consultation with and validated by a librarian at the Health Canada Library. It is available directly from the authors as Supplemental material (see Appendix for more information). The search was completed on July 3, 2024.

Full texts were identified, retrieved and screened against our inclusion criteria by two reviewers (Table 1). Our inclusion criteria ensured included studies were full economic evaluations with Pneu-C-21 as the intervention. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram ^{Footnote 11} that details this process was developed.

We extracted study characteristics, methods, findings and funding sources from evaluations that met our inclusion criteria. To ensure our findings were informative for NACI’s decision-making, we focused our review on health outcomes and costs for vaccination strategies that were under consideration (i.e., currently recommended strategies as comparators) (Appendix, Table S1). Costs were converted to 2023 Canadian dollars (CAD) using the Organisation for Economic and Co-operation and Development (OECD) purchasing parity rates ^{Footnote 12} and the Bank of Canada’s inflation calculator ^{Footnote 13}. Our main outcome of interest was the incremental cost-effectiveness ratio (ICER). When comparators from a study were not aligned with NACI’s policy questions, we calculated ICERs using the relevant comparator based on the costs and QALYs provided in the published study. Included economic evaluations were critically appraised by one reviewer using the Joanna Briggs Institute Critical Appraisal Checklist for Economic Evaluations (JBI Checklist) ^{Footnote 14}. To complement the JBI Checklist, we also appraised included studies against three questions from World Health Organization for standardization of economic evaluations of immunization programmes ^{Footnote 10Footnote 15}. To assess the generalizability of the included studies (i.e., JBI Checklist item 11: “Are the results generalizable to the setting of interest in the review?”), we considered guidance from Heyland et al. ^{Footnote 16}.

Results

Ten publications were identified in our search and five were included in our systematic review (Figure 1). Three economic evaluations were included from the peer-reviewed literature ^{Footnote 17Footnote 18Footnote 19}. Results from three economic evaluations were summarized and presented to ACIP ^{Footnote 20}, including a model by Altawalbeh et al. ^{Footnote 17} that was also identified in the peer-reviewed literature. For clarity, the models summarised to ACIP are referred to by the names of the model authors (i.e., Altawalbeh et al., 2024 ^{Footnote 17}; Owusu-Edusei et al., 2024 ^{Footnote 21}; Stoecker, 2024 ^{Footnote 22}). One of the evaluations presented to ACIP was an industry-funded model by Merck ^{Footnote 21}.

Figure 1: Descriptive text

The figure shows the PRISMA flow diagram of study identification, selection, and inclusion for the systematic review. Six records were identified from databases. Four records were identified from National Immunization Technical Advisory Groups (NITAGs). We excluded five of the original ten records. Three records from databases were not economic evaluations. Two records from NITAGs were duplicates. In total, five studies were included in the systematic review.

Footnote

Figure 1 Footnote a

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram ^{Footnote 11} detailing the search and screening process used to select included economic evaluations on the use of a 21-valent pneumococcal conjugate vaccine (Pneu-C-21) in adults

Return to footnote a referrer

All five economic evaluations used static cohort models to inform their cost-utility analyses (Table 2). Four evaluations were conducted in the United States ^{Footnote 17Footnote 19Footnote 21Footnote 22} and one was conducted in the Netherlands ^{Footnote 18}. Three economic evaluations were conducted from the societal perspective ^{Footnote 18Footnote 21Footnote 22}, one was conducted from the health system perspective ^{Footnote 19} and one included findings from both the societal and health system perspectives ^{Footnote 17}. The four studies conducted in the United States used a 3% discount rate ^{Footnote 17Footnote 19Footnote 21Footnote 22} and de Boer et al. used a 4% discount rate for costs and a 1.5% discount rate for QALYs ^{Footnote 18}. The three peer-reviewed studies met nine out of 11 of the JBI Checklist criteria and were high quality (Table 3). The two models only presented at ACIP met between three and six of the 11 JBI Checklist criteria. Only one study ^{Footnote 18} thoroughly discussed the strengths and weaknesses of their model in relation to pneumococcal transmission dynamics.

Each of the included economic evaluations assumed different age-specific serotype distributions of PD cases. However, serotypes included in Pneu-C-21 caused more IPD cases than serotypes included in Pneu-C-20 in all of the economic evaluations (Appendix, Figure S1). Detailed assumptions on the assumed impact of paediatric pneumococcal conjugate vaccination on PD in adults due to indirect effects are shown in Appendix, Table S2. Each economic evaluation included indirect effects from pediatric vaccination in primary ^{Footnote 18Footnote 22} or sensitivity analyses ^{Footnote 17Footnote 19Footnote 21}.

Four of the economic evaluations included vaccinating all individuals aged 65 years with Pneu-C-20 as a comparator (Appendix, Table S3). Pneu-C-21 was the optimal vaccination strategy at a cost-effectiveness threshold of $50,000/QALY gained in this population, when compared to Pneu-C-20, in the majority of included studies (Figure 2). In the analysis by de Boer et al. ^{Footnote 18}, Pneu-C-20 was dominated by Pneu-C-21, meaning that Pneu-C-21 was both less costly and more effective than Pneu-C-20. Incremental cost-effectiveness ratios ranged from $4,793/QALY gained ^{Footnote 22} to $52,265/QALY gained ^{Footnote 19} when comparing Pneu-C-21 to Pneu-C-20 in the other economic evaluations (Figure 2; Appendix, Table S3).

Figure 2: Descriptive text

Figure 2

Study (reference)	Preferred strategy by cost-effectiveness threshold (cost/QALY gained)
	Pneu-C-20	Sensitive to assumptions	Pneu-C-21
de Boer et al., 2024 Footnote 18	Not applicable	Not applicable	$0–$100,000
Owusu-Edusei et al., 2024 Footnote 21	$0–$5,904	Not applicable	$5,904–$100,000
Stoecker, 2024 Footnote 22	$0–$4,793	$4,793–$25,459	$25,459–$100,000
Wateska et al., 2023 Footnote 19 Black population	$0–$10,638	$10,638–$10,775	$10,775–$100,000
Wateska et al., 2023 Footnote 19 Non-Black population	$0–$50,174	$50,174–$52,265	$52,265–$100,000

Abbreviations: Pneu-C-20, 20-valent pneumococcal conjugate vaccine; Pneu-C-21, 21-valent pneumococcal conjugate vaccine; QALY, quality-adjusted life years

Two of the included economic evaluations compared the cost-effectiveness of vaccinating adults aged 50 years with Pneu-C-21 compared to no vaccination (Appendix, Table S3). Altawalbeh et al. ^{Footnote 17} compared vaccinating Black and non-Black adults at the age of 50 years with Pneu-C-21 to no vaccination. In contrast, Stoecker ^{Footnote 22} compared a strategy of vaccinating adults at the ages of 50 years and 65 years with Pneu-C-21 to a strategy of vaccinating adults at only the age of 65 years with Pneu-C-21, effectively comparing Pneu-C-21 at the age of 50 years to no vaccination in a population receiving Pneu-C-21 at the age of 65 years. Incremental cost-effectiveness ratios ranged from $66,706/QALY gained to $313,121/QALY gained ^{Footnote 17Footnote 22}, with the former reflecting the cost-effectiveness of vaccinating Black population members (Figure 3).

Figure 3: Descriptive text

Figure 3

Study (reference)	Preferred strategy by cost-effectiveness threshold (cost/QALY gained)
	No vaccination	Sensitive to assumptions	Pneu-C-21
Altawalbeh et al., 2024 Footnote 17 Black population	$0–$66,706	$66,706–$93,047	$93,047–$300,000
Altawalbeh et al., 2024 Footnote 17 Non-Black population	$0–$115,000	$115,000–$154,077	$154,077–$300,000
Stoecker, 2024 Footnote 22	$0–$208,435	$208,435–$300,000	Not applicable

Abbreviations: Pneu-C-21, 21-valent pneumococcal conjugate vaccine; QALY, quality-adjusted life years

One economic evaluation compared the cost-effectiveness of vaccinating adults younger than 50 years of age at high risk of PD (Appendix, Table S3). In a cohort of adults aged 42 years living with immunocompromising conditions, including HIV, cancer, organ transplants and dialysis, Pneu-C-20 was dominated by Pneu-C-21 ^{Footnote 22}.

Catch-up vaccination was examined by Owusu-Edusei et al. ^{Footnote 21} and Stoecker ^{Footnote 22} in a range of age and risk groups (Appendix, Table S3). A catch-up dose of Pneu-C-21 between one and five years after a dose of Pneu-C-20 was never cost-effective at commonly used thresholds, with ICERs ranging from $239,128/QALY gained ^{Footnote 22} to $594,229/QALY gained ^{Footnote 21}.

Discussion

Our review identified five economic evaluations that assessed the cost-effectiveness of using Pneu-C-21 in adults. Three economic evaluations were summarized from the peer-reviewed literature ^{Footnote 17Footnote 18Footnote 19} and two were summarized from ACIP presentations ^{Footnote 21Footnote 22}. In economic evaluations that included the strategy of vaccinating adults aged 65 years and older with Pneu-C-21 compared to Pneu-C-20, ICERs were around or below $50,000/QALY gained ^{Footnote 18Footnote 19Footnote 21Footnote 22}. A strategy of vaccinating adults aged 50 to 64 years with Pneu-C-21 compared to no vaccination had ICERs over $65,000/QALY gained, with the highest estimate being over $300,000/QALY gained ^{Footnote 17Footnote 22}. In adults younger than 50 years of age, a strategy with Pneu-C-21 dominated Pneu-C-20 in adults with immunocompromising conditions, but no vaccination dominated Pneu-C-21 in a strategy of vaccinating all adults (regardless of the presence of a chronic medical or immunocompromising condition) ^{Footnote 22}. Incremental cost-effectiveness ratios for a catch-up dose of Pneu-C-21 after vaccination with Pneu-C-20 were over $230,000/QALY gained ^{Footnote 21Footnote 22}. In the two studies that presented race-stratified results ^{Footnote 17Footnote 19}, ICERs were lower in the Black population compared to the non-Black population, primarily due to a higher risk of PD.

Although none of the included economic evaluations were conducted in Canada, they all employed cost-utility models, with health outcomes expressed as QALYs, which aligns with NACI’s guidelines for economic evaluations ^{Footnote 23}. Vaccine prices used in the economic evaluations conducted in the United States are higher than vaccine prices expected in Canada. An analysis commissioned by the United States Department of Health and Human Services and conducted by the RAND Corporation found that drug prices in Canada were, on average, 56% lower than those in the United States ^{Footnote 24}. Findings were especially sensitive to vaccine price assumptions when the comparator was no vaccination. In Canada, the recommended discount rate of future (i.e., beyond one year) costs and QALYs is 1.5% ^{Footnote 23}; with the exception of the discount rate of QALYs used by de Boer et al. ^{Footnote 18}, discount rates were greater than recommended by NACI’s guidelines ^{Footnote 17Footnote 18Footnote 19Footnote 21Footnote 22}. Altawalbeh et al. ^{Footnote 17} was the only economic evaluation to present results from both the health system and societal perspective. The model by Owusu-Edusei et al. ^{Footnote 21} is an industry-led model by Merck, the manufacturer of Pneu-C-21 ^{Footnote 5}. Finally, many of the vaccination strategies included in the economic evaluations were not relevant to current vaccine recommendations for adults living in Canada.

Limitations

The results of the included economic evaluations were sensitive to key assumptions. First, the incidence of PD caused by vaccine-type and non-vaccine-type serotypes differs by region and over time, and the impact of the COVID-19 pandemic on PD dynamics is still unknown ^{Footnote 19}. Because higher valency pneumococcal conjugate vaccines for children are new, assumptions of the potential impact of indirect effects from pediatric vaccination with Pneu-C-15 or Pneu-C-20 were necessary ^{Footnote 18Footnote 20Footnote 22}. In a multi-model comparison, Leidner ^{Footnote 20} identified the presence of indirect effects from pediatric vaccination, the PD case fatality rate, the prevalence and severity of long-term post-PD disability, productivity losses and vaccine price as key assumptions and parameters that impacted model findings. Altawalbeh et al. ^{Footnote 17} and Wateska et al. ^{Footnote 19} highlighted uncertainties surrounding vaccine price and vaccine effectiveness.

Additional limitations include the difficulty of assessing the quality of the economic evaluations presented to ACIP (because only presentation materials were available), the use of static models and assumptions regarding serotype replacement. To date, pneumococcal conjugate vaccines have been effective against S. pneumoniae colonization and their use has resulted in indirect (herd) effects. Dynamic transmission models are better equipped to capture the population level impact of pneumococcal conjugate vaccination strategies ^{Footnote 25}. Finally, with the exception of the model by de Boer et al. ^{Footnote 18}, none of the models included serotype replacement ^{Footnote 17Footnote 19Footnote 21Footnote 22}. Following the introduction of Pneu-C-13 in the routine pediatric vaccination schedule in Canada, serotype replacement resulted in a rise in IPD caused by the serotypes not included in the vaccine ^{Footnote 26Footnote 27}.

Conclusion

Our systematic review of economic evaluations assessing the cost-effectiveness of Pneu-C-21 in adults to support guidance on its use in adults living in Canada adults suggests that it may be a cost-effective intervention compared to current recommendations in some populations. However, to best understand the potential cost-effectiveness of the use of Pneu-C-21 in adults living in Canada, a de novo economic evaluation that better reflects the Canadian context is required.

Authors' statement

• AS — Conceptualization, formal analysis, writing–original draft
• RX — Conceptualization, writing–review & editing
• GG — Conceptualization, writing–review & editing
• MS — Conceptualization, writing–review & editing
• EW — Conceptualization, writing–review & editing
• AT — Conceptualization, writing–review & editing

Competing interests

None.

ORCID numbers

• Alison E Simmons — 0000-0001-8780-9467
• Raphael Ximenes — 0000-0003-2536-951X
• Gebremedhin B Gebretekle — 0000-0002-2485-505X
• Marina I Salvadori — 0000-0001-5371-6510
• Eva Wong — 0000-0001-8349-3733
• Ashleigh R Tuite — 0000-0002-4373-9337

Acknowledgements

We would like to acknowledge Alison Lake and the Health Canada Library for assistance conducting the systematic search of the literature and the members of the National Advisory Committee on Immunization Pneumococcal Working Group.

Funding

None.

Appendix

Additional data is available upon request to the author: alison.simmons@mail.utoronto.ca

• EBM Reviews: Cochrane Central Register of Controlled Trials
• EBM Reviews: EconLit
• EBM Reviews: Embase
• EBM Reviews: International Pharmaceutical Abstracts
• EBM Reviews: Ovid MEDLINE(R) ALL
• EBM Reviews: SCOPUS
• Table S1: Current pneumococcal vaccination strategies for adults in Canada
• Figure S1: Assumed age-specific pneumococcal serotype distributions in included economic evaluations
• Table S2: Summary of assumptions relating to indirect effects and serotype replacement from pediatric pneumococcal conjugate vaccination in included economic evaluations
• Table S3: Incremental cost-effectiveness ratios (ICERs) from selected strategies